NOVEL (HETEROCYCLE/TETRAHYDROPYRIDINE)-(PIPERAZINYL)-1-ALCANONE AND (HETEROCYCLE/DIHYDROPYRROLIDINE)-(PIPERAZINYL)-1-ALCANONE DERIVATIVES, AND USE THEREOF AS p75 INHIBITORS

ABSTRACT

The disclosure relates to (heterocycle-tetrahydropyridine)(piperazinyl)-1-alkanone and (heterocycle-dihydropyrrolidine)(piperazinyl)-1-alkanone derivatives of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein A, B, m, n, W, and R2 are as defined in the disclosure; to the methods of preparing said derivatives, and to the therapeutic uses thereof.

The present invention relates to(heterocycle-tetrahydropyridine)(piperazinyl)-1-alkanone and(heterocycle-dihydropyrrolidine)(piperazinyl)-1-alkanone derivatives, totheir preparation and to their therapeutic use.

The compounds according to the present invention have affinity for thep75^(NTR) receptor of neurotrophins.

Neurotrophins belong to a family of proteins especially having cellsurvival and differentiation as a biological effect.

The p75^(NTR) receptor, a receptor of all neurotrophins, is atransmembrane glycoprotein of the tumor necrosis factor (TNF) receptorfamily (W. J. Friedman and L. A. Greene, Exp. Cell. Res., 1999, 253,131-142). The p75^(NTR) receptor is expressed in several cell types, andseveral biological functions are attributed thereto: firstly, modulationof the affinity of neurotrophins for the tyrosine kinase (trk)receptors; secondly, in the absence of trk, induction of a cell deathsignal by apoptosis. Moreover, the neurotrophin precursors,proneurotrophins, are capable of binding to p75^(NTR) with highaffinity, and are considered as powerful p75^(NTR)-dependent apoptosisinducers in neurons and certain cell lines.

In the central nervous system, numerous studies show that apoptosisoccurs in several pathologies, such as amyotrophic lateral sclerosis,multiple sclerosis, Alzheimer's disease, Parkinson's disease,Huntington's disease and prion diseases. p75^(NTR) is also known to beoverexpressed in various types of neurodegenerative disease, for exampleAlzheimer's disease and amyotrophic lateral sclerosis (ALS) (Longo F. M.et al., Curr. Alzheimer Res. 2007; 4: 503-506; Lowry K. S. et al.,Amyotroph. Lateral. Scler. Other. Motor. Neuron. Disord. 2001;2:127-34).

Results suggest that p75^(NTR) may play a predominant role in mechanismsleading to neuronal death via post-ischemic apoptosis (P. P. Roux etal., J. Neurosci., 1999, 19, 6887-6896).

Results (V. Della-Bianca et al., J. Biol. Chem., 2001, 276: 38929-33)(S. Rabizadeh et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 10703-10706)support the hypothesis according to which p75^(NTR) plays an importantrole in neuronal death induced by the infectious prion protein(transmissible spongiform encephalopathy) or by the β-amyloid protein(Alzheimer's disease).

The p75^(NTR) receptor is also associated with the Nogo receptor andinvolved in the signaling of the inhibitory effects of these myelinproteins with respect to axonal growth. As a result, the p75^(NTR)receptor plays a major role in regulating neuronal plasticity and inneuron-glia interactions and thus represents a therapeutic target ofchoice for promoting nerve regeneration.

Beyond the nervous system and neurodegenerative diseases, it has beensuggested that p75^(NTR) may play a role in cardiovascular diseases suchas atherosclerosis and myocardial ischemia (M. L. Bochaton-Pialat etal., Am. J. Pathol., 1995, 146, 1-6; H. Perlman, Circulation, 1997, 95,981-987). Recent studies show an increase in the expression of p75^(NTR)and of neurotrophins, and massive apoptosis in atherosclerosis lesions.

Several studies also suggest that p75^(NTR) is an inflammation mediator(Rihl M. et al., Ann. Rheum. Dis. 2005; 64(11):1542-9; Raychaudhuri S.P. et al., Prog. Brain. Res. 2004; 146: 433-7, Tokuoka S. et al., Br. J.Pharmacol. 2001, 134: 1580-1586).

p75^(NTR) is also described as playing an important role in inflammatorypain. Specifically, lesion of the nerve is thought to selectivelyincrease the expression and axonal transport of p75^(NTR), involved inthe induction of neuropathic pain. Furthermore, the use ofp75^(NTR)-specific antibodies or of antisense oligodeoxynucleotidecapable of blocking the activity of the receptor in vivo is thought tobe capable of reversing neuropathic pain (heat- and cold-inducedhyperalgesia and mechanical allodynia) induced in rats after lesion ofthe L5 spinal nerve (Obata K. et al., J. Neurosci. 2006; 26:11974-11986). An anti-p75^(NTR) neutralizing antibody considerablyreduces the inflammatory pain induced by the injection of adjuvant intothe arch of the paw in mice, and also in a model of sciatic nerve crushin mice (Watanabe T. et al., J. Neurosci. Res. 2008; 86: 3566-357; FukuiY. et al., J Orthop Res. 2010; 28(3): 279-83).

The expression of p75^(NTR) is also described in chronic pancreatitis,with an involvement in apoptosis of the exocrine and endocrine pancreas(Zhu Z. et al., Dig. Dis. Sci. 2003; 48 (4): 717-25).

Other reports have also described the importance of p75^(NTR) in thedevelopment of hepatic fibrosis (Kendall T. J. et al., Hepatology. 2009;49 (3): 901-10).

p75^(NTR) also plays a critical role in tumor biology.

Many compounds are known for interacting with the trkA/NGF/p75^(NTR)system or for having activity of NGF (nerve growth factor) type. Thus,patent application WO 00/59893 describes substituted pyrimidinederivatives with activity of NGF type and/or which increase the NGFactivity on PC12 cells.

One subject of the present invention is compounds corresponding toformula (I):

in which:

-   -   n represents 1 or 2;    -   m represents 0 or 1;    -   A represents a fused heterocyclic group of formula (Y)

and B represents a hydrogen atom;orA represents a hydrogen atom; andB represents a fused heterocyclic group of formula (Y)

The fused heterocycle of formula Y may be attached to the rest of themolecule via any of the available carbon atoms, and in which:

-   -   U completes:        -   either an aromatic or saturated 6-atom nucleus, containing            one or two nitrogen atoms, the nucleus possibly being            substituted with one or two halogen atoms, one or two            (C1-C4)alkyl or (C1-C4)alkoxy groups, or one or two            perfluoroalkyl radicals;        -   or an aromatic or saturated 5-atom nucleus, containing a            nitrogen, oxygen or sulfur atom, the nucleus possibly being            substituted with one or two groups (C1-C4)alkyl;    -   X and X1 represent CH or N;    -   R and R1 located on any of the available positions,        independently represent a hydrogen atom, a halogen atom, a group        (C1-C4)alkyl, (C1-C4)alkoxy, a perfluoroalkyl or        trifluoromethoxy radical, a cyano or a group COOH, COOalkyl,        CONR3R4 or NHCOR3;        -   —W— is a nitrogenous heterocycle chosen from:

-   -   1-2 represents 1 or 2;    -   1-3 represents 1, 2 or 3;    -   R2 represents a group of formula:

-   -   -   in which R5 and R6, located on any of the available            positions, independently represent a hydrogen atom, a            halogen atom, a group (C1-C4)alkyl or (C1-C4)alkoxy, a            trifluoromethyl or trifluoromethoxy radical, a cyano or a            group COOH, COOalkyl, COOcycloalkyl, SOalkyl, SO₂alkyl,            CONR3R4, NR3R4 or NHCOR3;            or one of the groups R5 and R6 may also represent a            heterocycle chosen from:

-   -   Z represents an oxygen or sulfur atom;    -   R3 and R4 represent a hydrogen or a group C1-C6 alkyl.

The compounds of formula (I) may comprise one or more asymmetric carbonatoms. They may thus exist in the form of enantiomers ordiastereoisomers. These enantiomers and diastereoisomers, and alsomixtures thereof, including racemic mixtures, form part of theinvention.

The compounds of formula (I) may exist in the form of bases or ofacid-addition salts. Such addition salts form part of the invention.

These salts may be prepared with pharmaceutically acceptable acids, butthe salts of other acids that are useful, for example, for purifying orisolating the compounds of formula (I) also form part of the invention.

In the context of the present invention, the following definitionsapply:

-   -   a halogen atom: a fluorine, a chlorine, a bromine or an iodine;    -   an alkyl group: a saturated, linear, branched or cyclic        aliphatic group. Examples that may be mentioned include a group        (C1-C4)alkyl which may represent a methyl, ethyl, propyl,        isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl or        cyclobutyl;    -   a fluoroalkyl group: an alkyl group in which one or more        hydrogen atoms have been replaced with a fluorine atom;    -   a perfluoroalkyl group: an alkyl group in which all the hydrogen        atoms have been replaced with a fluorine atom, for example        trifluoroalkyl;    -   an alkoxy group: a radical —O-alkyl in which the alkyl group is        as defined previously;    -   a perfluoroalkoxy group: an alkoxy group in which all the        hydrogen atoms have been replaced with a fluorine atom, for        example trifluoroalkoxy;    -   a cycloalkyl group: a cyclic alkyl group. Examples that may be        mentioned include cyclopropyl, methylcyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, etc., groups.

Among the compounds of formula (I) that are subjects of the invention,another group of compounds is formed by the compounds of formula (I) inwhich:

-   -   n represents 1 or 2; and/or    -   m represents 0 or 1; and/or    -   A represents a fused heterocyclic group of formula (Y)

and B represents a hydrogen atom;orA represents a hydrogen atom;and B represents a fused heterocyclic group of formula (Y)

the fused heterocycle of formula Y possibly being attached to the restof the molecule via any of the available carbon atoms of the benzenenucleus;

-   -   U completes:        -   either an aromatic or saturated 6-atom nucleus, containing            one or two nitrogen atoms, the nucleus possibly being            substituted with one or two halogen atoms, one or two            (C1-C4)alkyl or (C1-C4)alkoxy groups, or one or two            perfluoroalkyl radicals;        -   or an aromatic or saturated 5-atom nucleus, containing a            nitrogen, oxygen or sulfur atom, the nucleus possibly being            substituted with one or two groups (C1-C4)alkyl; and/or    -   X and X1 represent CH or N; and/or    -   R and R1, located on any of the available positions,        independently represent a hydrogen atom, a halogen atom or a        group (C1-C4)alkyl or COOalkyl; and/or    -   —W— is a nitrogenous heterocycle chosen from:

or alternatively

-   -   R2 represents a group of formula:

and/or

-   -   R5 and R6, located on any of the available positions,        independently represent a halogen atom, a trifluoromethyl        radical or a group COOH, COOalkyl or COOcycloalkyl; or        one of the groups R5 and R6 may also represent a heterocycle        chosen from:

and/or

-   -   Z represents an oxygen or sulfur atom; and/or    -   R3 and R4 represent a hydrogen or a methyl group.

Among the compounds of formula (I) that are subjects of the invention,mention may be made especially of the following compounds:

-   Compound    1:1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(3,5-dimethyl-2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-yl)ethanone;-   Compound 2:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(8-pyrimidin-2-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;-   Compound 3:    1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(8-pyrimidin-2-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;-   Compound 4:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 5:    1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,5R)-2,5-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)ethanone;-   Compound 6:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,5R)-2,5-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)ethanone;-   Compound 7:    1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 8:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;-   Compound 9:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 10:    2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-7-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 11:    2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-[4-(2-propylbenzo[b]thiophen-7-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 12:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[5-(5-trifluoromethylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone;-   Compound 13:    1-(4-benzo[b]thiophen-6-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 14:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 15:    1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-(8-pyrimidin-2-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;-   Compound 16:    1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 17:    4-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;-   Compound 18:    2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 19:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,6R)-2,6-dimethyl-4-quinolin-2-ylpiperazin-1-yl)ethanone;-   Compound    20:1-(4-quinolin-8-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 21:    1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 22:    2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 23:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;-   Compound 24:    1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;-   Compound 25:    2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone;-   Compound 26:    1-(4-benzofuran-3-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;-   Compound 27:    2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 28:    1-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;-   Compound 29:    1-(4-benzo[b]thiophen-3-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;-   Compound 30:    4-{2-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;-   Compound 31:    4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;-   Compound 32:    4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;-   Compound 33:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 34:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 35:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)ethanone;-   Compound 36:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;-   Compound 37:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;-   Compound 38:    2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 39:    2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 40:    2-((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 41:    1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)ethanone;-   Compound 42:    1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)ethanone;-   Compound 43:    4-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;-   Compound 44:    1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;-   Compound 45:    1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;-   Compound 46:    1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl)ethanone;-   Compound 47:    1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl)ethanone;-   Compound 48:    5-{(3S,5R)-4-[2-(4-benzo[b]thiophen-4-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}pyridine-2-carboxylic    acid;-   Compound 49:    4-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(6-trifluoromethylpyridin-3-yl)piperazin-2-one;-   Compound    50:1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;-   Compound 51: Methyl    5-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}pyridine-2-carboxylate;-   Compound 52: Methyl    6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinate;-   Compound 53:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)ethanone;-   Compound 54:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl)ethanone;-   Compound 55:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)ethanone;-   Compound 56:    6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinic    acid;-   Compound 57:    6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinic    acid;-   Compound 58: Methyl    6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinate;-   Compound 59:    6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinic    acid;-   Compound 60:    4-[2-(4-benzofuran-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;-   Compound 61: Methyl    6-((3S,5R)-3,5-dimethyl-4-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-1-yl)nicotinate;-   Compound 62:    6-((3S,5R)-3,5-dimethyl-4-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-1-yl)nicotinic    acid;-   Compound 63:    1-(5-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 64: Ethyl    6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinate;-   Compound 65: Methyl    6-{3-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;-   Compound 66: Methyl    7-(1-{2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]acetyl}-1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene-2-carboxylate;-   Compound 67: Methyl    5-(1-{2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]acetyl}-1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene-2-carboxylate;-   Compound 68:    2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-[4-(2-propylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 69: Methyl    6-{3-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;-   Compound 70: Methyl    6-{3-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;-   Compound 71:    6-{3-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic    acid;-   Compound 72:    2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-[4-(7-fluorobenzofuran-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 73:    1-[4-(2,3-dimethylbenzofuran-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 74:    2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone;-   Compound 75:    1-(4-benzofuran-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)ethanone;-   Compound 76: Methyl    6-{3-[2-oxo-2-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-pyridin-1-yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;-   Compound 77: Methyl    6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinate;-   Compound 78:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(4-pyridin-3-yl-[1,4]diazepan-1-yl)ethanone;-   Compound 79:    6-{3-[2-oxo-2-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-pyridin-1-yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic    acid;-   Compound 80:    6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinic    acid;-   Compound 81: Methyl    6-{3-[2-(3-benzofuran-7-yl-2,5-dihydropyrrol-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;-   Compound 82: Methyl    6-{3-[2-(3-benzo[b]thiophen-7-yl-2,5-dihydropyrrol-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;-   Compound 83:    4-[2-(3-benzofuran-7-yl-2,5-dihydropyrrol-1-yl)-2-oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;-   Compound 84:    6-{3-[2-(4-benzofuran-7-yl-2,3-dihydropyrrol-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic    acid;-   Compound 85:    6-{3-[2-(5-benzo[b]thiophen-7-yl-3,4-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic    acid;-   Compound 86:    6-{3-[2-(4-benzo[b]thiophen-7-yl-2,3-dihydropyrrol-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic    acid;-   Compound 87: Methyl    6-(3-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinate;-   Compound 88:    2-{(3S,5R)-4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}pyrimidine-5-carboxylic    acid;-   Compound 89:    3-(6-{3-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}pyridin-3-yl)-4H-[1,2,4]oxadiazol-5-one;-   Compound 90:    3-(6-{3-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}pyridin-3-yl)-4H-[1,2,4]oxadiazol-5-one;-   Compound 91:    6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinonitrile;-   Compound 92:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-(3-chloro-5-trifluoromethylpyridin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;-   Compound 93:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(8-pyridin-3-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;-   Compound 94:    6-{3-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinonitrile;-   Compound 95:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[5-(5-trifluoromethylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone;-   Compound 96: cyclobutyl    6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinate;-   Compound 97:    2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 98:    1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-(4-quinolin-2-ylpiperazin-1-yl)ethanone;-   Compound 99:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]ethanone;-   Compound 100:    2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 101:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-(5-chloropyridin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;-   Compound 102:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2R,5S)-2,5-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]ethanone;-   Compound 103:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;-   Compound 104:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(6-trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;-   Compound 105:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(4-quinolin-2-ylpiperazin-1-yl)ethanone;-   Compound 106:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]ethanone;-   Compound 107:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-chloropyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 108:    2-[4-(6-chloropyridin-2-yl)piperazin-1-yl]-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 109:    1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 110:    2-((2S,6R)-2,6-dimethyl-4-quinolin-2-yl-piperazin-1-yl)-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 111:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(4-pyridin-3-yl-[1,4]diazepan-1-yl)ethanone;-   Compound 112:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5,6-dichloropyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 113:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(6-bromopyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 114:    1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-(4-quinolin-2-ylpiperazin-1-yl)ethanone;-   Compound 115:    1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[5-(6-trifluoromethylpyridazin-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone;-   Compound 116:    1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound 117:    2-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;-   Compound 118:    4-[2-oxo-2-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-pyridin-1-yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;-   Compound 119:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-thiazol-2-ylpyridin-2-yl)piperazin-1-yl]ethanone;-   Compound    120:1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-{(2S,6R)-2,6-dimethyl-4-[5-(2-methyl-2H-tetrazol-5-yl)pyridin-2-yl]piperazin-1-yl}ethanone;-   Compound 121:    2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone;-   Compound 122:    4-[2-oxo-2-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;-   Compound 123:    1-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;-   Compound 124:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-{8-[5-(1-methyl-1H-tetrazol-5-yl)pyridin-2-yl]-3,8-diazabicyclo[3.2.1]oct-3-yl}ethanone;-   Compound 125:    1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-(5-methanesulfonylpyridin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;    in the form of a base or of an acid-addition salt.

In the text hereinbelow, the term “protecting group Pg” mean a groupthat makes it possible, firstly, to protect a reactive function such asa hydroxyl or an amine during a synthesis, and, secondly, to regeneratethe intact reactive function at the end of the synthesis. Examples ofprotecting groups and of protection and deprotection methods are givenin Protective Groups in Organic Synthesis, Green et al., 2^(nd) Edition(John Wiley & Sons, Inc., New York).

In accordance with the invention, the compounds of general formula (I)may be prepared according to the process that follows.

More specifically, the process for preparing the compounds of generalformula (I) in which A, B, m, n, W and R2 are as defined previouslycomprises the reaction of a compound of formula (II):

in which A, B, m and n are defined as in the general formula (I) and Halrepresents a halogen atom, for example chlorine,and of a compound of general formula (III):

H—W—R2  (III)

in which W and R2 are defined as in the general formula (I), accordingto methods known to those skilled in the art, for example in thepresence of a base, in a solvent as described in WO 03/104225. Thus,bases that may be mentioned include organic bases such as triethylamine,N,N-diisopropylamine, diisopropylethylamine (DPEA) or N-methylmorpholineor alkali metal carbonates or bicarbonates such as potassium carbonate,sodium carbonate or sodium bicarbonate and in the absence or presence ofan alkali metal iodide such as potassium iodide or sodium iodide. Thereaction is performed in a solvent such as acetonitrile,N,N-dimethylformamide (DMF), N-methylpyrrolidinone, toluene or2-propanol, and at a temperature between room temperature and the refluxtemperature of the solvent. The term “room temperature” means atemperature of between 5 and 25° C. By way of example, the reaction maybe performed in the presence of sodium bicarbonate, sodium iodide in asolvent such as DMF. These reactions may also be performed in amicrowave reactor.

In the products of general formula (I) thus obtained, R, R1, R3, R4, R5and R7 may be modified via treatments commonly used by those skilled inthe art, for instance hydrolysis of an ester group to give a carboxylicgroup or of a cyano to obtain a tetrazole group.

Generally, the acid-addition salts of the compounds of general formula(I) may be obtained by adding the appropriate acid, such as hydrochloricacid, hydrobromic acid or oxalic acid.

The compounds of formula (III), optionally in the form of salts, may beprepared from the corresponding compounds of formula (VIII):

Pg—W—R2  (VIII)

in which W and R2 are as defined in formula (I) and Pg represents aprotecting group for a nitrogen atom of W. Preferably, Pg is a benzylgroup and the deprotection is performed according to standard methodsthat are well known to those skilled in the art, for example viacatalytic hydrogenation over Pd/C or by treatment with chloroformatesfollowed by hydrolysis in acidic medium.

The compounds of formula (VIII) may be prepared from the compounds offormula (VI):

Pg—W—H  (VI)

and (VII):

Hal-R2  (VII)

in which Pg, W and R2 are defined as previously and Hal represents ahalogen atom, preferably chlorine. This reaction is generally performedunder the same conditions as the reaction for the preparation of thecompounds of formula (I) from the compounds of formulae (II) and (III).

Alternatively, the compounds of formula (VIII) may be prepared via theBuchwald coupling method in the presence of a suitably selectedpalladium catalyst and a suitably selected phosphine, using as solventinert solvents such as toluene or xylene, at a temperature between roomtemperature and 110° C.

In the compounds of general formula (VIII) thus obtained, R7 and R8 maybe modified via treatments commonly used by those skilled in the art,for instance the synthesis of an oxadiazole group starting with a cyanogroup or via the formation of a boronic intermediate and via Suzukicoupling as described in the scheme below.

In Scheme 2 above, L represents a leaving group such as iodo, bromo ortrifluoromethanesulfonate, R7 represents heterocycles as described inthe general formula (I), R8 is as defined in the general formula (I) andB is a boron atom.

Examples of such reactions are described in the experimental section.

The compounds of formula (III), optionally in the form of salts, when Wrepresents an oxopiperazine, are commercially available or described inthe literature, or may be prepared from the corresponding compounds offormula (VIII) according to methods that are described or known to thoseskilled in the art.

Examples of such preparations are described in the experimental section.

The compounds of formula (II) may be obtained by reacting acorresponding compound of formula (IV):

in which A, B and m are defined as in the general formula (I),optionally in the form of an acid-addition salt, with a compound offormula (V):

in which Hal and n are as defined in formula (II) and Hal′ represents ahalogen atom, which may be identical to or different than Hal.Preferably, Hal′ represents a chlorine atom.

This reaction is generally performed in the presence of a base such astriethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in asolvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane ora mixture of these solvents, and at a temperature of between 0° C. androom temperature. The compounds of formula (V) are generallycommercially available.

Optionally, the process according to the invention comprises thesubsequent step that consists in isolating the desired product obtained.

The products of formulae (IV), (V), (VI) and (VII) and the reactants,when their preparation method is not described, are commerciallyavailable or described in the literature, or else may be preparedaccording to methods that are described or known to those skilled in theart.

Alternatively, the compounds of formula (I) may be prepared according tothe following process:

More specifically, the process for preparing the compounds of generalformula (I) in which A, B, R2, m and n are as defined previouslycomprises the reaction of a compound of formula (XIV):

in which R2, W and n are defined as in the general formula (I)and of a compound of general formula (IV)

in which A, B and m are defined as in the general formula (I), accordingto methods known to those skilled in the art, for example in a solventsuch as dichloromethane, DMF or THF, in the presence of a base such aspyridine, triethylamine, N,N-diisopropylamine or diisopropylethylamine(DPEA) and of a coupling agent such as BOP, DBU or DCC. The reaction isperformed at a temperature between room temperature and the refluxtemperature of the solvent. The term “room temperature” means atemperature between 5 and 25° C. By way of example, the reaction may beperformed in the presence of sodium bicarbonate, sodium iodide in asolvent such as DMF. These reactions may also be performed in amicrowave reactor.

In the compounds of general formula (I) thus obtained, R, R1, R3, R4,R5, R6, R7 and R8 may be modified with treatments commonly used by thoseskilled in the art, for instance by hydrolysis of an ester group to givea carboxylic group or of a cyano to obtain a tetrazole group.

Generally, the acid-addition salts of the compounds of general formula(I) may be obtained by adding the appropriate acid, such as hydrochloricacid, hydrobromic acid or oxalic acid.

The compounds of formula (XIV) may be obtained from compounds of formula(XIII)

in which R2, W and n are defined as in the general formula (I) and Qrepresents a residue that is capable of forming an ester, such asmethyl, ethyl or benzyl, by hydrolysis of the ester bond, according tomethods that are well known to those skilled in the art, for example viaa treatment in an acidic or basic aqueous medium, or alternatively viareduction in a polar solvent such as an alcohol or THF, under a streamof hydrogen.

The compounds of formula (XIII) may be obtained from compounds offormula (III)

H—W—R2  (III)

in which R2 and W are defined as in the general formula (I), optionallyin the form of an acid-addition salt, and from a compound of formula(XII):

in which Q represents a residue that is capable of forming an ester,such as methyl, ethyl or benzyl, Hal represents a halogen atom,preferably a chlorine atom, and n is as defined in the general formula(I).

This reaction is generally performed in the presence of a base, such astriethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in asolvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane ora mixture of these solvents, and at a temperature between 0° C. and roomtemperature. The compounds of formula (XII) are generally commerciallyavailable.

The compounds of formula (III), optionally in the form of salts, may beprepared from the corresponding compounds of formula (VIII):

Pg—W—R2  (VIII)

in which W and R2 are as defined in formula (I) and Pg represents aprotecting group for a nitrogen atom of W. Preferably, Pg is a benzylgroup and the deprotection is performed according to standard methodsthat are known to those skilled in the art, for example via catalytichydrogenation over Pd/C or by treatment with chloroformates followed byhydrolysis in acidic medium.

The compounds of formula (VIII) may be prepared from the compounds offormula (VI):

Pg—W—H  (VI)

and (VII):

Hal-R2  (VII)

in which Pg, W and R2 are defined as previously and Hal represents ahalogen atom, preferably chlorine. This reaction is generally performedunder the same conditions as the reaction for preparing the compounds offormula (I) from the compounds of formulae (II) and (III).

Alternatively, the compounds of formula (VIII) may be prepared via theBuchwald coupling method in the presence of a suitably selectedpalladium catalyst and a suitably selected phosphine, using as solventinert solvents such as toluene or xylene, at a temperature of betweenroom temperature and 110° C. In the compounds of general formula (VIII)thus obtained, R7 and R8 may be modified via treatments generally usedby those skilled in the art, for instance the synthesis of an oxadiazolegroup starting with a cyano group, or alternatively via Suzuki couplingsas already described in Scheme 2 presented hereinabove.

The compounds of formula (III), optionally in the form of salts, where Wrepresents an oxopiperazine, are commercially available or described inthe literature, or else may be prepared, from the correspondingcompounds of formula (VII), according to methods that are described orknown to those skilled in the art.

Examples of such preparations are described in the experimental section.

Optionally, the process according to the invention comprises thesubsequent step that consists in isolating the desired product obtained.

The products of formulae (IV), (VI), (VII) and (XII) and the reactants,when their preparation method is not described, are commerciallyavailable or described in the literature, or else may be preparedaccording to methods that are described or known to those skilled in theart.

Examples of such preparations are described in the experimental section.

According to another of its aspects, a subject of the invention is alsocompounds of formula (II)

in which A, B, n and m are defined as in the general formula (I) and Halrepresents a halogen atom, preferably chlorine; optionally in the formof an acid-addition salt. These compounds are useful as intermediates inthe synthesis of the compounds of formula (I).

The examples that follow describe the preparation of certain compoundsin accordance with the invention. These examples are not limiting, andserve merely to illustrate the present invention. The numbers of thecompounds presented as examples refer to those given in the tablehereinbelow, which illustrates the chemical structures and physicalproperties of a number of compounds according to the invention.

The physicochemical measurements were performed in the following manner:

The melting points were measured using a Buchi B540 machine.

The proton nuclear magnetic resonance (1H NMR) spectra were recordedunder the following conditions:

a) at 500 MHz on a Bruker machine equipped with an Avance III console;b) at 400 MHz on a Bruker machine equipped with an Avance I console.

The chemical shifts are reported in ppm relative to the TMS frequency.

The spectra were recorded under the following temperature conditions:

-   -   Temp. A: 40° C.    -   Temp. B: 30° C.

The abbreviations used to characterize the signals are the following:s=singlet, bs=broad singlet, m=multiplet, bm=broad multiplet, d=doublet,bd=broad doublet, t=triplet, q=quadruplet.

*=not integratable because of the interference with a broad peak due towater.**=not integratable because of the interference with a peak due to theNMR solvent.2×s=two partially superposed singlets.2×bs=two partially superposed broad singlets.2×m=two partially superposed multiplets.

The compounds are analyzed by HPLC-UV-MS (liquid chromatography-UVdetection and mass detection) coupling.

The machine used is composed of a Thermo Surveyor chromatographic lineequipped with a Thermo diode array detector and a Thermo Deca XPMaxion-trap mass spectrometer.

The analytical conditions are as follows:

HPLC Conditions

Various HPLC conditions were used according to the compounds:

Method A

Eluent A: H₂O+TFA 0.005%+CH₃CN 5% Eluent B: CH₃CN Gradient:

Time (min % B

Time (min) % B 0 5 17 90 22 90 23 5 30 5Column temperature: 30° C.Flow rate: 0.3 ml/min

Detection: λ=220 nm

Method B

Eluent A: H₂O+TFA 0.005% Eluent B: CH₃CN Gradient:

Time (min) % B 0 5 22 90 29 90 30 5 40 5Column temperature: not controlledFlow rate: 0.3 ml/min

Detection: λ=220 nm

Method C

Eluent A: AcONH₄ 5 mM at pH 6.5 Eluent B: CH₃CN Gradient:

Time (min) % B 0 5 25 90 30 90 32 5 40 5Column temperature: not controlledFlow rate: 0.3 ml/min

Detection: λ=220 nm

Method D

Eluent A: AcONH₄ 5 mM at pH 6.5 Eluent B: CH₃CN Gradient:

Time (min) % B 0 5 17 90 22 90 23 5 30 5Column temperature: not controlledFlow rate: 0.3 ml/min

Detection: λ=220 nm

Method E

Eluent A: H₂O+TFA 0.01% Eluent B: CH₃CN Gradient:

Time (min) % B 0 10 18 95 20 95 21 10 25 10Column temperature: 40° C.Flow rate: 0.5 ml/min

Detection: λ=220 nm

Method F

Eluent A: H₂O+TFA 0.005% Eluent B: CH₃CN Gradient:

Time (min) % B 0 10 18 60 20 60 21 10 25 10Column temperature: not controlledFlow rate: 0.3 ml/min

Detection: λ=220 nm

Method G

Eluent A: AcONH₄ 5 mM at pH 6.5 Eluent B: CH₃CN Gradient:

Time (min) % B 0 40 25 40Column temperature: not controlledFlow rate: 0.3 ml/min

Detection: λ=220 nm

Method H

Eluent A: H₂O+TFA 0.05% Eluent B: CH₃CN+TFA 0.035% Gradient:

Time (min) % B 0 10 22 90 29 90 30 10 40 10Column temperature: 40° C.Flow rate: 0.3 ml/min

Detection: λ=220 nm

Method I

Eluent A: H₂O+TFA 0.01% Eluent B: CH₃CN Gradient:

Time (min) % B 0 2 10 95 15 95 16 2 20 2Column temperature: 40° C.Flow rate: 0.5 ml/min

Detection: λ=220 nm

The columns used are C18 columns with a particle size of between 2 and 5μm, preferably 3.5 μm.

Mass Spectrometry Conditions

The mass spectra are recorded in positive or negative electrospray (ESI)mode, in order to observe the ions derived from the protonation of theanalyzed compounds (MH⁺ or MH⁻), or the formation of adducts with othercations such as Na⁺, K⁺, etc.

Thin-layer chromatography was performed on Merck Silica Gel 60 silicagel TLC plates. The silica gel for the flash column chromatography issold by Biotage or Supelco.All the solvents used are of “reagent grade” or “HPLC grade” purity.

Preparation 1(3R,5S)-3,5-dimethyl-1-(5-trifluoromethylpyridin-2-yl)piperazine

0.8 g of 2-chloro-5-(trifluoromethyl)pyridine (compound of formula(VII)), 0.5 g of cis-2,6-dimethylpiperazine (compound of formula (VI)),0.67 g of potassium carbonate and 0.3 g of NaI are placed in 8 ml ofDMF. The reaction is performed in a CEMdiscover microwave initiator for30 minutes at 160° C. The mixture is then poured into saturated aqueoussodium chloride solution and extracted with ethyl acetate. The organicphase is dried over Na₂SO₄, filtered and evaporated under vacuum. 1.1 gof an oily material corresponding to the title product are isolated.

Preparation 2(3R,5S)-2,5-dimethyl-1-(5-trifluoromethylpyridin-2-yl)piperazine

By performing the process as described in Preparation 1, but using2,5-trans-dimethylpiperazine instead of cis-2,6-dimethylpiperazine, thetitle compound is obtained in the form of an oily material.

Preparation 32-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octanehydrochloride

1.44 g of 2-chloro-5-fluoropyrimidine (compound of formula (VII)), 2.2 gof 1-benzyl-3,8-diazabicyclo[3.2.1]octane (compound of formula (VI)),1.7 g of potassium carbonate and 0.73 g of NaI are placed in 27 ml ofN-methylpyrrolidone. The mixture is heated at 110° C. for 5 hours. It isthen poured into saturated aqueous sodium chloride solution andextracted with ethyl acetate. The organic phase is dried over Na₂SO₄,filtered and evaporated under vacuum. 3.2 g of an oily material areisolated, and this material is purified by flash chromatography on aBiotage® column, using 95/5 cyclohexane/ethyl acetate as eluent. 1.4 gof a white solid are isolated, and are dissolved in 35 ml of1,2-dichloroethane. 0.72 ml of 1-chloroethyl chloroformate is added at0° C. and the mixture is stirred under a stream of nitrogen for 10minutes at 0° C. and then for 3 hours at 85° C. The solvent isevaporated off and 35 ml of methanol are added. The mixture is heatedfor 30 minutes at the reflux temperature. The solvent is evaporated offand the residue is treated with isopropanol. A white solid is obtained,which is filtered off, and 900 mg of title product are isolated.m.p.=236-239° C.

Preparation 4(3R,5S)-3,5-dimethyl-1-(6-trifluoromethylpyridin-2-yl)piperazine

2.2 g of 2-trifluoromethyl-5-bromopyridine (compound of formula (VII)),1.1 g of cis-2,6-dimethylpiperazine (compound of formula (VI)), 0.22 gof palladium acetate, 0.28 g of sodium t-butoxide and 1.3 g oftri-t-butylphosphine are placed in 16 ml of o-xylene. The mixture isheated at 120° C. for 6 hours. The resulting mixture is filtered throughcelite and the solvent is evaporated off. 1.8 g of an oily materialcorresponding to the title product are isolated.

Preparation 5 Methyl 3,8-diazabicyclo[3.2.1]oct-8-ylnicotinatehydrochloride

0.42 g of methyl 6-chloronicotinate (compound of formula (VII)), 0.5 gof 1-benzyl-3,8-diazabicyclo[3.2.1]octane (compound of formula (VI)),0.4 g of potassium carbonate and 0.17 g of NaI are placed in 7 ml ofN-methylpyrrolidone. The mixture is heated for 7 hours at 110° C. It isthen poured into saturated aqueous sodium chloride solution andextracted with ethyl acetate. The organic phase is dried over Na₂SO₄,filtered and evaporated under vacuum. 1.1 g of an oily material areisolated, and this material is purified by flash chromatography on aBiotage® column, using 8/2 cyclohexane/ethyl acetate as eluent. 520 mgof a clear oil are isolated. The product obtained in the preceding stepis hydrogenated at 40° C. under atmospheric pressure for 2 hours, in 20ml of ethanol and 2 ml of isopropanol/HCl, in the presence of 0.22 g of10% Pd/C. The resulting mixture is filtered and evaporated under vacuum,and 440 mg of the title product are isolated in the form of a whitesolid corresponding to the title product.

Preparation 6 1-(5-trifluoromethylpyridin-2-yl)piperazin-2-onehydrochloride

10 g of 2-chloro-5-(trifluoromethyl)pyridine and 40.5 ml ofN-benzylethylenediamine are heated at 135° C. for 6 hours in around-bottomed flask. The resulting mixture is poured into water andextracted with ethyl acetate. The extracts are dried and evaporatedunder vacuum; the crude product thus obtained is purified by flashchromatography. The isolated product (compound of formula (VIII)), 14 g,is dissolved in 200 ml of 2N HCl solution. 30 g of trimeric glyoxaldihydrate are added and the mixture is stirred at room temperature for72 hours. The resulting mixture is extracted with ethyl acetate. Theextracts are dried and evaporated under vacuum; the crude product thusobtained is purified by flash chromatography. The isolated product, 10g, is dissolved in 450 ml of ethanol, followed by addition of 15 ml of asolution of isopropanol saturated with HCl and 3 g of 10% Pd/C. Thismixture is reacted under a stream of hydrogen for 4 hours at atemperature of 40° C. The resulting mixture is filtered and evaporatedunder vacuum to give 3 g of the title compound, m.p.=205-207° C.

Preparation 72-chloro-1-(2-phenyl-6,7-dihydro-4H-thiazolo[4,5-c]pyridin-5-yl)ethanoneStep a) preparation of1-(t-butoxycarboyl)-4-(7-benzo[b]thiophene)-4-hydroxypiperidine

45 g of 7-bromobenzothiophene are dissolved in 135 ml of THF and thesolution thus obtained is added dropwise to a suspension of 5.13 g ofmagnesium in 10 ml of THF in a round-bottomed flask under nitrogen. Acatalytic amount of iodine is added and the mixture is heated at thereflux temperature for 3 hours. The resulting mixture is cooled to roomtemperature and a solution of 36 g of 1-(t-butoxycarbonyl)-4-piperidonein 80 ml of THF is added. This mixture is stirred for 3 hours at roomtemperature, and saturated ammonium chloride solution is added.

The resulting mixture is extracted with ethyl acetate. The extracts aredried and evaporated under vacuum; the crude product thus obtained ispurified by flash chromatography using 95/5 hexane/ethyl acetate aseluent. 47.5 g of a white solid with a melting point of 130-131° C. areisolated.

Step b) preparation of 4-(7-benzo[b]thiophene)-4-hydroxypiperidinehydrochloride

40 g of the product from step a) are dissolved in 650 ml of ethylacetate. 88 ml of 37% HCl are added slowly and the mixture is stirred atroom temperature for 30 minutes. The solvents are evaporated off and theresidue is treated with acetone. The resulting mixture is filtered togive 34 g of a white solid with a melting point of 232-233° C.

Step c) preparation of4-(7-benzo[b]thiophene)-1,2,3,6-tetrahydropyridine hydrochloride

34 g of the product from step b) are dissolved in 437 ml of acetic acid.

20 ml of 96% sulfuric acid are added and the mixture is heated at atemperature of 60° C. for 2 hours. The resulting mixture is poured intoa water/ice mixture and the pH is made basic with 40% sodium hydroxidesolution. The resulting mixture is extracted with ethyl acetate. Theextracts are dried and evaporated under vacuum to give 30 g of productin the form of an oily material. The formation of the hydrochloride isobtained in isopropanol using a solution of isopropanol saturated withHCl. The product is filtered off to give 25.8 g of a white solid with amelting point of 226-227° C.

Step d) preparation of2-chloro-1-(2-phenyl-6,7-dihydro-4H-thiazolo[4,5-c]pyridin-5-yl)ethanone

2.8 g of the product from step c) are suspended in 50 ml ofdichloromethane in a round-bottomed flask equipped with a magneticstirrer. 2.8 ml of triethylamine are added and the mixture is cooled to0° C. At 0° C., 1.5 ml of chloroacetyl chloride, i.e. the compound ofgeneral formula (V) in which Hal=Hal′=Cl and n=1, are added dropwise.The mixture is reacted for 1 hour 30 minutes and is poured into water.The resulting mixture is extracted with dichloromethane. The organicphase is dried over Na₂SO₄, filtered and evaporated under vacuum. 4.1 gof an oil material are isolated, and this material is purified by flashchromatography on a Biotage® column, using 9/1 cyclohexane/ethyl acetateas eluent. 1.1 mg of the title product are isolated in the form of aclear oil.

Preparation 81-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-chloroethanone

By performing the process as described in Preparation 1, but using7-bromobenzofuran instead of 7-bromobenzothiophene, the title compoundis obtained.

Preparation 91-(5-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-chloroethanone

By performing the process as described in Preparation 1, but using7-bromobenzofuran instead of 7-bromobenzothiophene and1-(t-butoxycarbonyl)-3-piperidone instead of1-(t-butoxycarbonyl)-4-piperidone, the title compound is obtained.

Preparation 10 Methyl5-[1-(2-chloroacetyl)-1,2,3,6-tetrahydropyridin-4-yl]-benzo[b]thiophene-3-carboxylate

Step a) preparation of tert-Butyl4-(2-methoxycarbonylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate:

1.1 g of tert-butyl4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(purity 70%), 0.7 g of methyl 5-bromobenzo[b]thiophene-2-carboxylate,0.15 g of PalladiumTetrakis (PdP(Ph₃)₄), 5.5 ml of 2M sodium carbonatesolution and 0.42 g of lithium chloride are placed in 30 ml of DME in around-bottomed flask under a stream of nitrogen. The mixture is heatedat the reflux temperature for 3 hours. The solvent is evaporated off andthe residue is dissolved in 35 ml of ethyl acetate. This solution iswashed with 2M sodium carbonate solution. The organic phase is driedover Na₂SO₄, filtered and evaporated under vacuum. 1.6 g of an oilymaterial are isolated, and this material is purified by flashchromatography on a Biotage® column, using 98/2 cyclohexane/ethylacetate as eluent. 0.45 g of a yellowish solid is isolated.

Step b) preparation of methyl5-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene-2-carboxylate)hydrochloride

0.45 g of the product from step a) is dissolved in 25 ml of ethylacetate. 50 ml of a solution of ethyl acetate saturated with HCl areadded slowly and the mixture is stirred at room temperature for 3 hours.The solvents are evaporated off and the residue is treated with acetone.This mixture is filtered to give 0.35 g of a whitish solid.

Step c) preparation of methyl5-[1-(2-chloroacetyl)-1,2,3,6-tetrahydropyridin-4-yl]benzo[b]thiophene-3-carboxylate

By performing the process as described in step d) of Preparation 7, butusing the product of step b) instead of the product of step c) ofPreparation 7, 0.4 g of the title product is obtained in the form of aclear oil.

Preparation 112-chloro-1-(4-quinolin-8-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone

By performing the process as described in Preparation 10, but using8-bromoquinoline instead of methyl5-bromobenzo[b]thiophene-2-carboxylate, the title compound is obtained.

Preparation 122-chloro-1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone

By performing the process as described in Preparation 1, but using6-bromobenzodioxane instead of 7-bromobenzothiophene, the title compoundis obtained.

Preparation 131-(3-benzofuran-7-yl-2,5-dihydropyrrol-1-yl)-2-chloroethanone

By performing the process as described in Preparation 7, but using1-(t-butoxycarbonyl)-3-pyrrolidone instead of1-(t-butoxycarbonyl)-4-piperidone and 7-bromobenzofuran instead of7-bromobenzothiophene, the title compound is obtained.

Preparation 14 Methyl 6-((3S,5R)-3,5-dimethylpiperazin-1-yl)nicotinate

By performing the process as described in Preparation 1, but usingmethyl 6-chloronicotinate instead of 2-trifluoromethyl-5-bromopyridine,the title compound is obtained in the form of a clear oil.

Preparation 153-[6-(3,8-diazabicyclo[3.2.1]oct-8-yl)pyridin-3-yl]-4H-[1,2,4]oxadiazol-5-onehydrochloride Step a) 6-(3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinonitrilehydrochloride

By performing the process as described in Preparation 3, but using6-chloronicotinonitrile instead of 2-chloro-5-fluoropyrimidine, thetitle compound is obtained in the form of a white solid.

Step b) tert-Butyl8-(5-cyanopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

7 g of the product from step a) are dissolved in 83 ml of DMF. 11.7 mlof triethylamine are added. 6.7 g of (BOC)₂O are added at 0° C., and themixture is stirred at room temperature for 1 hour. The resulting mixtureis evaporated under vacuum. The residue is washed with water andextracted with ethyl acetate. The organic phase is dried over Na₂SO₄,filtered and evaporated under vacuum. 12 g of an oily material areisolated, and this material is purified by flash chromatography on anautomatic Biotage® column, using 8/2 cyclohexane/ethyl acetate in agradient up to 100% ethyl acetate as eluent. 7.6 g of the title compoundare isolated in the form of a white solid.

Step c) tert-Butyl8-[5-(N-hydroxycarbamimidoyl)pyridin-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

The product of step b) (7.6 g) is dissolved in 75 ml of ethanol, and asolution of 3.36 g of hydroxylamine hydrochloride dissolved in 38 ml ofwater is added, followed by addition of 5 g of sodium carbonate. Themixture is stirred at 90° C. for 4 hours. The resulting mixture iscooled and filtered. 8 g of the title compound are obtained in the formof a white solid.

Step d) tert-Butyl8-[5-(5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl)pyridin-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

1 g of the compound from step c) is placed in a round-bottomed flaskunder a stream of nitrogen, and 10 ml of DMF and 0.3 ml of pyridine areadded. 0.23 ml of methyl chloroformate is added at 0° C., and themixture is stirred at room temperature for 3 hours. The resultingmixture is washed with water and extracted with ethyl acetate. Theorganic phase is dried over Na₂SO₄, filtered and evaporated undervacuum. 30 ml of toluene are added and the resulting mixture is stirredat reflux for 4 hours. The solvent is evaporated off to give 0.8 g ofthe title compound.

Step e)3-[6-(3,8-diazabicyclo[3.2.1]oct-8-yl)pyridin-3-yl]-4H-[1,2,4]oxadiazol-5-onehydrochloride

The product is dissolved in 20 ml of ethyl acetate, a solution of ethylacetate saturated with HCl is added, and the mixture is stirred at roomtemperature for 2 hours. The solvent is evaporated off and the residueis treated with isopropanol. This mixture is filtered to give 0.65 g ofthe title compound in the form of a yellow solid.

Preparation 16[(2R,6S)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]aceticacid Step a) Ethyl[(2R,6S)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]acetate

3.6 g of the product of Preparation 1, 100 ml of THF, 1.9 ml of ethylbromoacetate and 4.7 ml of triethylamine are placed in a round-bottomedflask equipped with a magnetic stirrer. The mixture is reacted for 7hours at 80° C. The solvent is evaporated off and the residue is washedwith ethyl ether and filtered. The filtration water is purified by flashchromatography on an automatic Biotage® column using 8/2cyclohexane/ethyl acetate at a gradient up to 7/3 ethyl acetate/methanolas eluent. 2.5 g of the title product are isolated in the form of asolid.

Step b)[(2R,6S)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]aceticacid

2.5 g of the product from the preceding step are dissolved in 22 ml ofethanol, followed by addition of 5 ml of aqueous 40% NaOH solution. Themixture is reacted for 3 hours at 70° C. The pH is adjusted to 6 using1N HCl solution. The resulting mixture is extracted with ethyl acetate.The organic phase is dried over Na₂SO₄, filtered and evaporated undervacuum. 1.6 g of the title product are isolated in the form of a whitesolid.

Preparation 17 2-(1,2,3,6-tetrahydropyridin-4-yl)quinoline hydrochloride

By performing the process as described in Preparation 10, but usingquinolin-2-yl trifluoromethanesulfonate instead of methyl5-bromobenzo[b]thiophene-2-carboxylate, the title compound is obtainedin the form of a white solid.

Preparation 18(3S,5R)-3,5-dimethyl-1-(5-thiazol-2-ylpyridin-2-yl)piperazine

Step a) (3S,5R)-3,5-dimethyl-1-(5-iodo-2-ylpyridin-2-yl)piperazine

By performing the process as described in Preparation 1, but using2-fluoro-5-iodopyridine instead of 2-chloro-5(trifluoromethyl)pyridine,the title compound is obtained in the form of an oil.

Step b) tert-Butyl(2S,6R)-2,6-dimethyl-4-(5-iodo-2-ylpyridin-2-yl)piperazine-1-carboxylate

0.35 g of the compound from step a), 0.26 g of (Boc)₂O and 0.46 ml oftriethylamine are placed in 5 ml of DMF under a stream of nitrogen at 0°C. The mixture is heated at a temperature of 140° C. for 4 hours. Thesolvent is evaporated off. 0.49 g of crude product is isolated. Theresidue is purified by flash chromatography on a Biotage® column, usingethyl acetate as eluent. 0.43 g of the title compound is isolated havingthe form of a pale yellow oil.

Step c) tert-Butyl(2S,6R)-2,6-dimethyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate

0.43 g of the compound from step b), 0.29 g of bis(pinacol)diboron,0.026 g of palladium Cl₂ (dppf)₂.CH₂Cl₂ and 0.31 g of potassium acetateare placed in 10 ml of DMSO in a round-bottomed flask under a stream ofnitrogen. The mixture is heated at 85° C. for 2 hours. The resultingmixture is poured into saturated aqueous NaCl solution and extractedwith ethyl acetate. The organic phase is dried over Na₂SO₄, filtered andevaporated under vacuum. 0.32 g of an oily material is isolated, andthis material is purified by flash chromatography on a Biotage® column,using 9/1 cyclohexane/ethyl acetate as eluent. 0.28 g of a yellowishsolid is isolated.

Step d) tert-Butyl2S,6R-2,6-dimethyl-4-(5-thiazol-2-ylpyridin-2-yl)piperazine-1-carboxylate

0.28 g of the compound from step c), 0.092 g of 2-bromothiazole, 0.032 gof palladiumTetrakis (PdP(Ph3)₄) and 0.094 g of sodium bicarbonate areplaced in 20 ml of DME and 3 ml of water in a round-bottomed flask undera stream of nitrogen. The mixture is heated at the reflux temperaturefor 7 hours. The resulting mixture is poured into saturated aqueous NaClsolution and extracted with ethyl acetate. The organic phase is driedover Na₂SO₄, filtered and evaporated under vacuum. 0.36 g of an oilymaterial is isolated, and this material is purified by flashchromatography on a Biotage® column, using 9/1 cyclohexane/ethyl acetateas eluent. 0.2 g of a yellowish oil is isolated.

Step e) (3S,5R)-3,5-dimethyl-1-(5-thiazol-2-ylpyridin-2-yl)piperazinetrifluoroacetate

The compound from step d) (0.2 g) is dissolved slowly in 5 ml oftrifluoroacetic acid at 0° C. The mixture is then stirred for 2 hours atroom temperature. The trifluoroacetic acid is evaporated off undervacuum to give 0.15 g of the title compound in the form of abeige-colored solid.

Preparation 19 [3-oxo-4-(3-trifluoromethylphenyl)piperazin-1-yl]aceticacid Step a) Benzyl[3-oxo-4-(3-trifluoromethylphenyl)piperazin-1-yl]acetate

1.12 g of 1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one, 40 ml of THFand 0.87 ml of benzyl bromoacetate are placed in 1.5 ml of triethylaminein a round-bottomed flask equipped with a magnetic stirrer. The mixtureis reacted under a stream of nitrogen overnight at room temperature. Thesolvent is evaporated off and the residue is purified by flashchromatography on a Biotage® column, using 1/1 hexane/ethyl acetate aseluent. 2.9 g of title product are isolated in the form of a whitesolid.

Step b) [3-oxo-4-(3-trifluoromethylphenyl)piperazin-1-yl]acetic acid

1 g of the product from the preceding step is dissolved in 150 ml ofethanol, followed by addition of 0.15 g of 10% Pd/C. The mixture isreacted under a stream of hydrogen for 4 hours at a temperature of 40°C. The resulting mixture is filtered and evaporated under vacuum to give0.74 g of the title compound in the form of a white solid.

EXAMPLE 1 Compound 341-(4-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone

0.18 g of the compound obtained in Preparation 8 (compound of formula(II)), 0.17 g of the compound obtained in Preparation 1 (compound offormula (III)), 0.1 g of potassium carbonate and 0.04 g of NaI arereacted together in 3 ml of DMF. The reaction is performed using aCEMdiscover microwave initiator for 30 minutes at 160° C. The mixture ispoured into water and extracted with ethyl acetate. The organic phase isdried over Na₂SO₄, filtered and evaporated under vacuum. 0.36 g of anoily material is isolated. It is purified on a column by flashchromatography using a Biotage® column eluted with a 6/4cyclohexane/ethyl acetate mixture. 0.180 g of a pale yellow solid isisolated, and is crystallized from ethyl ether. The product is filteredoff to give 0.08 g of title product in the form of a white solid.

M.p.: 138-139° C.

NMR Machine b). δ (ppm, DMSO-d6): 1.06 (m, 6H); 2.56-2.79 (m, 4H); 3.19(m, *), 3.73 (m, 4H); 4.18 (m, 3H); 4.31 (m, 1H); 6.57 (m, 1H); 6.95 (d,J=9.2 Hz, 1H); 6.99 (d, J=1.8 Hz, 1H); 7.27 (m, 2H); 7.58 (d, J=7.2 Hz,1H); 7.76 (dd, J=9.2 and 2.2 Hz, 1H); 8.01 (d, J=1.7 Hz, 1H); 8.39 (bs,1H).

EXAMPLE 2 Compound 11-(4-Benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanoneand the oxalate thereof

By performing the process as described in Example 1, but using thecompound of Preparation 7 instead of the compound of Preparation 8, thetitle compound is obtained.

It is dissolved in acetone and a solution of oxalic acid in acetone isadded, and the oxalate is obtained in the form of a white solid.

M.p.: 60-61° C.

NMR: (Machine b). δ (ppm, DMSO-d6): 1.17 (m, 6H), 2.60+2.68 (2×m, 2H);2.97 (m, *); 3.36 (m, *); 3.76 (m, *); 4.00 (m, *); 4.14-4.43 (m, *);6.30 (bs, 1H); 7.03 (d, J=9.0 Hz, 1H); 7.32 (d, J=7.1 Hz, 1H); 7.42 (t,J=7.6 Hz, 1H); 7.51 (d, J=5.3 Hz, 1H); 7.77 (d, J=5.5 Hz, 1H); 7.83 (m,2H); 8.43 (bs, 1H).

EXAMPLE 3 Compound 141-(4-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanoneand the oxalate thereof

By performing the process as described in Example 1, but using thecompound of Preparation 2 instead of the compound of Preparation 1, andthe compound of Preparation 8 instead of the compound of Preparation 7,the title compound is obtained.

It is dissolved in acetone, a solution of oxalic acid in acetone isadded and the oxalate is obtained in the form of a white solid.

M.p.: 130-131° C.

NMR (Machine b). δ (ppm, DMSO-d6): 1.02 (m, 3H); 1.15-1.32 (m, 3H); 2.64(m, 2H); 2.78 (m, 1H); 2.92 (m, 1H); 2.90 (m, 1H); 3.26 (m, *);3.34-3.67 (m, *); 3.66-3.99 (m, *); 4.07-4.54 (m, *); 4.64 (m, *); 6.58(m, 1H); 6.90 (m, 1H); 6.98 (d, J=1.9 Hz, 1H); 7.20-7.33 (m, 2H); 7.58(d, J=7.2 Hz, 1H); 7.76 (m, 1H); 8.00 (d, J=1.8 Hz, 1H); 8.39 (m, 1H).

EXAMPLE 4 Compound 69 Methyl6-{3-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate

0.47 g of the compound obtained in Preparation 7 (compound of formula(II)), 0.45 g of the compound obtained in Preparation 5 (compound offormula (III)), 0.57 ml of diisopropylethylamine and 18 ml of DMF arereacted together. The mixture is heated at 100° C. for 3 hours. It ispoured into water and extracted with ethyl acetate. The organic phase isdried over Na₂SO₄, filtered and evaporated under vacuum. 0.58 g of asolid material is isolated. It is purified on a column by flashchromatography, eluting with a 1/1 hexane/ethyl acetate mixture. 0.24 gof the title product is isolated. It is treated with diethyl ether andfiltered to give 0.21 g of a white solid.

M.p.: 153-154° C.

NMR (Machine a). δ (ppm, DMSO-d6): 1.87 (m, 2H), 1.98 (m, 2H); 2.40 (m,2H); 2.56 (m, 1H); 2.71 (m, 3H); 3.17+3.20 (2×s, 2H); 3.69-3.88 (m, 5H);4.16 (s, 1H); 4.42 (s, 1H); 4.67 (bs, 2H); 6.29+6.32 (2×m, 1H); 6.78 (m,1H); 7.31 (d, J=7.2 Hz, 1H); 7.42 (t, J=7.6 Hz, 1H); 7.50 (d, J=54 Hz,1H); 7.77 (d, J=5.3 Hz, 1H); 7.82 (d, J=7.5 Hz, 1H); 7.93 (d, J=8.7 Hz,1H); 8.64 (bs, 1H).

EXAMPLE 5 Compound 361-(4-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone

By performing the process as described in Example 4, but using thecompound of Preparation 8 instead of the compound of Preparation 7, andthe compound of Preparation 4 instead of the compound of Preparation 5,the title compound is obtained in the form of a white solid.

M.p.: 174-175° C.

NMR (Machine a). δ (ppm, DMSO-d6): 1.71-2.03 (m, 4H); 2.39 (m, 2H);2.57-2.80 (m, 4H); 3.16+3.19 (2×s, 2H); 3.73+3.82 (2×m, 2H); 4.17 (bs,1H); 4.42 (bs, 1H); 4.60 (m, 2H); 6.56+6.59 (2×m, 1H); 6.98 (d, J=2.3Hz, 1H); 7.27 (m, 2H); 7.58 (dd, J=7.35 and 1.8 Hz, 1H); 8.01 (d, J=2.1Hz, 1H); 8.44 (m, 2H).

EXAMPLE 6 Compound 716-{3-[2-(4-Benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinicacid

0.147 g of the compound of Example 4 is dissolved in 2 ml of aqueous 3NHCl solution. The mixture is heated at the reflux temperature for 2hours. 2 ml of aqueous 3N HCl are added. The mixture is heated at thereflux temperature for 1 hour. The resulting mixture is washed withethyl ether. The pH is adjusted to 6 with NaHCO₃ solution and theresulting mixture is extracted with ethyl acetate. The organic phase isdried and evaporated to give 200 mg of an oily material. This materialis treated with diethyl ether and filtered to give 0.015 g of a paleyellow solid corresponding to the title product.

M.p.: 121-122° C.

NMR (Machine b). δ (ppm, DMSO-d6): 1.75-2.06 (m, 4H); 2.41 (m, 2H); 2.56(m, **); 2.70 (m, 3H); 3.12-3.33 (m, *); 3.68-3.90 (m, 2H); 4.16 (bs,1H); 4.42 (bs, 1H); 4.66 (bs, 2H); 6.29 (m, 1H); 6.78 (m, 1H); 7.31 (d,J=7 Hz, 1H); 7.42 (dd→t, J=˜8 Hz, 1H); 7.50 (d, J=5.6 Hz, 1H); 7.77 (d,J=5.4 Hz, 1H); 7.82 (d, J=8 Hz, 1H); 7.91 (m, 1H); 8.63 (bs, 1H);11.72-12.49 (bs, 1H).

EXAMPLE 7 Compound 324-[2-(4-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one

By performing the process as described in Example 4, but using thecompound of Preparation 8 instead of the compound of Preparation 7, andthe compound of Preparation 6 instead of the compound of Preparation 5,the title compound is obtained in the form of a white solid.

M.p.: 151-152° C.

NMR (Machine a). δ (ppm, DMSO-d6): 2.64 (m, 0.9H); 2.73 (m, 1.1H); 2.99(m, 2H); 3.51 (s, 3H); 3.77 (m, 2H); 3.98 (m, 2H); 4.22 (s, 1.1H); 4.33(s, 0.9H); 6.57 (bs, 1H); 6.98 (d, J=2.2 Hz, 1H); 7.22-7.34 (m, 2H);7.58 (bd, J=7.5 Hz, 1H); 7.99 (bs, 1H); 8.22 (m, 2H); 8.84 (m, 1H).

EXAMPLE 8 Compound 201-(4-Quinolin-8-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-trifluoromethyl-pyridin-2-yl)piperazin-1-yl]ethanoneand the oxalate thereof

By performing the process as described in Example 4, but using thecompound of Preparation 11 instead of the compound of Preparation 7, and(5-trifluoromethylpyridin-2-yl)piperazine instead of the compound ofPreparation 5, the title compound is obtained.

It is dissolved in acetone and a solution of oxalic acid in acetone isadded, to give the oxalate in the form of an amorphous beige-coloredsolid.

NMR (Machine b). δ (ppm, DMSO-d6): 2.77+2.87 (2×m, 2H); 3.02 (m, 4H);3.53-3.98 (m, *); 4.22 (m, 2H); 5.96 (m, 1H); 7.03 (d, J=9.1 Hz, 1H);7.50-7.65 (m, 3H); 7.86 (dd, J=9.0 and 2.1 Hz, 1H); 7.92 (m, 1H); 8.38(dd, J=8.2 and 1.8 Hz, 1H); 8.46 (bs, 1H); 8.90 (m, 1H).

EXAMPLE 9 Compound 451-[4-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone

By performing the process as described in Example 1, but using thecompound of Preparation 12 instead of the compound of Preparation 7, thetitle compound is obtained in the form of a white solid.

M.p.: 200-201° C.

NMR (Machine a). δ (ppm, DMSO-d6): 1.05 (m, 6H); 2.39+2.50 (2×m, **);2.60 (m, 2H); 3.21-3.32 (m, *); 3.56-3.73 (m, 4H); 3.77 (m, 2H);4.05+4.18 (2×m, 2H); 4.24 (s, 4H); 6.05 (m, 1H); 6.82 (d, J=8.4 Hz, 1H);6.89-6.96 (m, 2H); 7.39 (dd, J=8.8 and 2.6 Hz, 1H); 7.60 (d, J=8.8 Hz,1H); 8.39 (d, J=2.7 Hz, 1H).

EXAMPLE 10 Compound 631-(5-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone

By performing the process as described in Example 1, but using thecompound of Preparation 9 instead of the compound of Preparation 7, thetitle compound is obtained in the form of a white solid.

M.p.: 129-130° C.

NMR (Machine a). δ (ppm, DMSO-d6): 1.06 (m, 6H); 2.33+2.44 (2×m, 2H);2.71 (m, 2H); 3.19 (m, *); 3.68 (m, 2H); 3.73 (s, 2H); 4.17 (m, 2H);4.47+4.58 (2×bs, 2H); 6.63 (bs, 1H); 6.94 (m, 1H); 6.70 (bs, 1H);7.22-7.39 (m, 2H); 7.59 (d, J=7.4 Hz, 1H); 7.75 (bd, J=9.0 Hz, 1H); 8.02(bs, 1H); 8.38 (bs, 1H).

EXAMPLE 11 Compound 67 Methyl5-(1-{2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)-piperazin-1-yl]acetyl}-1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene-2-carboxylateand the oxalate thereof

By performing the process as described in Example 1, but using thecompound of Preparation 10 instead of the compound of Preparation 7, thetitle compound is obtained.

It is dissolved in acetone and a solution of oxalic acid in acetone isadded, to give the oxalate in the form of an amorphous beige-coloredsolid.

NMR (Machine b). δ (ppm, DMSO-d6): 1.15 (m, 6H); 2.58+2.68 (2×m, 2H);2.95 (m, 2H); 3.35 (m, 2H); 3.74 (m, *); 3.82-4.08 (m, *); 4.12-4.40 (m,*); 6.31 (m, 1H); 7.03 (d, J=9.0 Hz, 1H); 7.70 (m, 1H); 7.83 (bd, J=9.1Hz, 1H); 8.01-8.11 (m, 2H); 8.20 (bs, 1H); 8.43 (bs, 1H).

EXAMPLE 12 Compound 834-[2-(3-Benzofuran-7-yl-2,5-dihydropyrrol-1-yl)-2-oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one

By performing the process as described in Example 4, but using thecompound of Preparation 13 instead of the compound of Preparation 7, andthe compound of Preparation 6 instead of the compound of Preparation 5,the title compound is obtained in the form of a white solid.

M.p. 184-186° C.

NMR (Machine b). δ (ppm, DMSO-d6): 2.89-3.12 (m, 4H); 3.45-3.59 (m, 4H);3.80-4.02 (m, 4H); 4.74+4.83 (2×s, 2H); 7.51 (m, 3H); 8.20 (m, 2H), 8.37(m, 2H); 8.65-8.88 (m, 2H).

EXAMPLE 13 Compound 893-(6-{3-[2-(4-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}pyridin-3-yl)-4H-[1,2,4]oxadiazol-5-one

By performing the process as described in Example 4, but using thecompound of Preparation 8 instead of the compound of Preparation 7, andthe compound of Preparation 15 instead of the compound of Preparation 5,the title compound is obtained in the form of a white solid.

M.p.: 230-232° C.

NMR: (Temp. B). δ (ppm, DMSO-d6): 1.76-2.04 (m, 4H), 2.41 (m, 2H),2.56-2.81 (m, 4H), 3.17+3.21 (2×s, 2H), 3.73 (m, 1H), 3.81 (m, 1H), 4.17(m, 1H), 4.42 (m, 1H), 4.64 (m, 2H), 6.56 (m, 0.5H), 6.61 (m, 0.5H),6.89 (m, 1H), 6.99 (d, J=2.2 Hz, 1H), 7.24-7.32 (m, 2H), 7.58 (dd, J=7.3and 1.4 Hz, 1H), 7.82 (m, 1H), 8.02 (m, 1H), 8.48 (m, 1H), 12.69 (bs,1H).

EXAMPLE 14 Compound 51 Methyl6-{(3R,5S)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinate

By performing the process as described in Example 1, but using thecompound of Preparation 8 instead of the compound of Preparation 7, andthe compound of Preparation 14 instead of the compound of Preparation 1,the title compound is obtained.

It is dissolved in acetone and a solution of oxalic acid in acetone isadded, to give the oxalate in the form of an amorphous white solid.

NMR: (Machine b, Temp. A). δ (ppm, DMSO-d6): 1.19 (m, 6H), 2.67+2.76(2×m, 2H), 3.04 (m, **), 3.43 (m, **), 3.58-4.58 (m, **), 6.58 (m, 1H),6.88-7.12 (m, 2H), 7.28 (m, 2H), 7.59 (m, 1H), 7.90-8.12 (m, 2H), 8.68(m, 1H).

EXAMPLE 15 Compound 576-{(3S,5R)-4-[2-(4-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinicacid

By performing the process as described in Example 6, but using thecompound of Example 13 instead of the compound of Example 4, the titlecompound is obtained in the form of an oily material. It is treated withdiethyl ether and filtered, to give a pale yellow solid corresponding tothe title product.

M.p.: 272-274° C.

NMR: (Temp. B). δ (ppm, DMSO-d6): 1.06 (m, 6H), 2.55-2.76 (m, 4H), 3.17(m, 2H), 3.72 (m, 4H), 4.18 (m, 3H), 3.41 (s, 1H), 6.57 (m, 1H), 6.81(d, J=9.0 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H), 7.22-7.32 (m, 2H), 7.58 (d,J=7.4 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 8.02 (s, 1H), 8.62 (m, 1H).

EXAMPLE 16 Compound 1184-[2-Oxo-2-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-pyridin-1-yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one

0.11 g of the compound of Preparation 19 is suspended in around-bottomed flask equipped with a magnetic stirrer, in 13 ml ofdichloromethane. 0.1 g of4-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-c]pyridine, 0.19 ml oftriethylamine and 0.15 g of BOP are added. The mixture is reacted for 1hour at room temperature.

It is then poured into water and extracted with dichloromethane. Theorganic phase is dried over Na₂SO₄, filtered and evaporated undervacuum. 0.22 g of an oily material is isolated. It is purified on acolumn by flash chromatography using a Biotage® column eluted with ethylacetate. 0.7 g of white solid is isolated.

M.p.: 145-148° C.

NMR: (Machine a, Temp. B). δ (ppm, DMSO-d6): 2.69 (m, 0.9H), 2.79 (m,1.1H), 3.00 (m, 2H), 3.51 (m, 4H), 3.77 (m, 2H), 3.97 (m, 2H), 4.25 (m,1.1H), 4.35 (m, 0.9H), 6.34+6.37 (2×m, 1H), 7.75 (m, 1H), 7.84+7.88(2×m, 1H), 7.97 (m, 1H), 8.22 (m, 2H), 8.40 (m, 1H), 8.84 (m, 1H).

EXAMPLE 17 Compound 1191-(4-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-thiazol-2-ylpyridin-2-yl)piperazin-1-yl]ethanoneoxalate

By performing the process as described in Example 1, but using thecompound of Preparation 8 instead of the compound of Preparation 7, andthe compound of Preparation 18 instead of the compound of Preparation 1,the title compound is obtained in free base form. It is dissolved inacetone and a solution of oxalic acid in acetone is then added. Thetitle product is obtained in the form of a white solid.

M.p.: 140-145° C.

NMR: (Machine a, Temp. B). δ (ppm, DMSO-d6): 1.21 (m, 6H), 2.67 (m, *),2.77 (m, *), 2.91-3.95 (m, *), 4.04-4.47 (m, *), 6.59 (m, 1H), 7.00 (d,J=2.1 Hz, 1H), 7.05 (m, 1H), 7.27 (m, 1H), 7.32 (m, 1H), 7.59 (d, J=7.4Hz, 1H), 7.68 (bd, J=3.2 Hz, 1H), 7.86 (bd, J=3.2 Hz, 1H), 8.03 (bd,1H), 8.08 (m, 1H), 8.71 (bs, 1H)

EXAMPLE 18 Compound 1212-[(2S,6R)-2,6-Dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone

By performing the process as described in Example 16, but using thecompound of Preparation 16 instead of the compound of Preparation 19,and the compound of Preparation 17 instead of4-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-c]pyridine, the titlecompound is obtained in the form of a white solid.

M.p.: 94-95° C.

NMR: (Machine a, Temp. B). δ (ppm, DMSO-d6): 1.06 (m, 6H), 2.66-2.78 (m,3H), 2.85 (m, 1H), 3.20 (m, 2H), 3.66-3.79 (m, 4H), 4.20 (m, 3H), 4.35(m, 1H), 6.89 (m, 1H), 6.95 (d, J=9.1 Hz, 1H), 7.56 (m, 1H), 7.72-7.79(m, 2H), 7.87 (d, J=8.7 Hz, 1H), 7.92-7.99 (m, 2H), 8.33 (m, 1H), 8.39(m, 1H).

The following table describes the examples obtained by applicationand/or adaptation of methods described using suitable reagents andstarting materials:

(I)

No. A B m W R2 n Salt M.P. ° C. LCMS  1

H 1

1 oxalate 60-61 MH+ 448 r.t. 8.4′ Method A  2

H 1

1 HCl 111-112 MH+ 446 r.t. 8.4′ Method A  3

H 1

1 — MH+ 446 r.t. 9.5′ Method A  4

H 1

1 oxalate MH+ 515 r.t. 19.1′ Method A  5

H 1

1 oxalate 101-102 MH+ 448 r.t. 16.4′ Method G  6

H 1

1 oxalate 96-97 MH+ 448 r.t. 8.6′ Method A  7

H 1

1 — MH+ 515 r.t. 22.7′ Method C  8

H 1

1 — 162-163 MH+ 513 r.t. 14.6′ Method B  9

H 1

1 oxalate 107-108 MH+ 515 r.t. 22.2′ Method C  10

H 1

1 oxalate 93-94 MH+ 529 r.t. 12.7′ Method B  11

H 1

1 oxalate 90-91 MH+ 557 r.t. 17.0′ Method D  12

H 1

1 oxalate 105-106 MH+ 499 r.t. 12.7′ Method D  13

H 1

1 oxalate 141-143 MH+ 515 r.t. 6.3′ Method A  14

H 1

1 oxalate 130-131 MH+ 499 r.t. 8.6′ Method B  15

H 1

1 — 171-173 MH+ 460 r.t. 5.7′ Method A  16

H 1

1 — 159 MH+ 5.1 r.t. 7.6′ Method A  17

H 1

1 — 141-143 MH+ 515 r.t. 8.2′ Method A  18

H 1

1 — 162-163 MH+ 529 r.t. 6.3′ Method A  19

H 1

1 HCl 192-193 MH+ 497 r.t. 5.5′ Method A  20

H 1

1 oxalate — MH+ 482 r.t. 4.7′ Method A  21

H 1

1 — 142-143 MH+ 489 r.t. 5.3′ Method A  22

H 1

1 — 177-179 MH+ 478 r.t. 6.7′ Method A  23

H 1

1 — 157-158 MH+ 448 r.t. 5.6′ Method C  24

H 1

1 — 163-165 MH+ 466 r.t. 5.0′ Method A  25

H 1

1 — 167-168 MH+ 465 r.t. 3.8′ Method A  26

H 1

1 — 207-210 MH+ 448 r.t. 5.6′ Method A  27

H 1

1 oxalate 128-130 MH+ 447 r.t. 4.8′ Method A  28

H 1

1 oxalate 95-96 MH+ 465 r.t. 5.3′ Method A  29

H 1

1 — 172-174 MH+ 464 r.t. 5.5′ Method A  30

H 1

1 — 230-233 MH+ 484 r.t. 6.8′ Method A  31

H 1

1 — 143-146 MH+ 501 r.t. 7.7′ Method A  32

H 1

1 — 151-152 MH+ 485 r.t. 7.5′ Method A  33

H 1

1 — 155-156 MH+ 471 r.t. 5.7′ Method A  34

H 1

1 — 138-139 MH+ 499 r.t. 5.8′ Method A  35

H 1

1 — 142-143 MH+ 432 r.t. 4.6′ Method A  36

H 1

1 HCl 174-175 MH+ 450 r.t. 5.4′ Method A  37

H 1

1 — 119-120 MH+ 499 r.t. 5.7′ Method A  38

H 1

1 — 205-206 MH+ 480 r.t. 5.1′ Method A  39

H 1

1 — 217-218 MH+ 529 r.t. 5.4′ Method A  40

H 1

1 — 191-192 MH+ 462 r.t. 4.5′ Method A  41

H 1

1 — 218-220 MH+ 448 r.t. 4.5′ Method A  42

H 1

1 oxalate — MH+ 466 r.t. 5.6′ Method E  43

H 1

1 — 169-170 MH+ 501 r.t. 7.0′ Method A  44

H 1

1 oxalate 90-91 MH+ 468 r.t. 4.3′ Method A  45

H 1

1 — 200-201 MH+ 517 r.t. 4.5′ Method A  46

H 1

1 — 170-171 MH+ 487 r.t. 5.3′ Method A  47

H 1

1 — 136-137 MH+ 515 r.t. 6.3′ Method E  48

H 1

1 — — MH+ 491 r.t. 4.4′ Method A  49

H 1

1 — 161-162 MH+ 503 r.t. 6.2′ Method A  50

H 1

1 — 120-121 MH+ 487 r.t. 5.7′ Method A  51

H 1

1 oxalate — MH+ 489 r.t. 5.1′ Method A  52

H 1

1 — 130-132 MH+ 505 r.t. 6.7′ Method E  53

H 1

1 — — MH+ 466 r.t. 5.2′ Method A  54

H 1

1 HCl 225-226 MH+ 515 r.t. 5.6′ Method A  55

H 1

1 — 195-196 MH+ 448 r.t. 4.6′ Method A  56

H 1

1 — — MH+ 491 r.t. 6.1′ Method A  57

H 1

1 — 272-274 MH+ 475 r.t. 4.7′ Method A  58

H 1

1 HCl 208-210 MH+ 505 r.t. 6.6′ Method E  59

H 1

1 — — MH+ 491 r.t. 6.2′ Method F  60

H 1

1 — 154-155 MH+ 485 r.t. 7.3′ Method A  61

H 1

1 — 148-150 MH+ 519 r.t. 8.2′ Method A  62

H 1

1 — — MH+ 505 r.t. 5.4′ Method A  63 H

1

1 — 129-130 MH+ 499 r.t. 5.8′ Method A  64

H 1

1 HCl — MH+ 503 r.t. 5.5′ Method A  65

H 1

1 — 158-159 MH+ 487 r.t. 5.1′ Method A  66

H 1

1 HCl 138-141 MH+ 573 r.t. 6.0′ Method A  67

H 1

1 oxalate — MH+ 573 r.t. 6.0′ Method A  68

H 1

1 — 157-159 MH+ 557 r.t. 6.8′ Method A  69

H 1

1 — 153-154 MH+ 503 r.t. 5.5′ Method A  70

H 1

1 — 150-151 MH+ 503 r.t. 5.5′ Method A  71

H 1

1 — 121-122 MH+ 489 r.t. 5.0′ Method A  72

H 1

1 oxalate — MH+ 517 r.t. 5.6′ Method A  73

H 1

1 oxalate — MH+ 527 r.t. 6.1′ Method A  74

H 1

1 — — MH+ 510 r.t. 4.5′ Method A  75

H 1

1 — MH+ 404 r.t. 11.5′ Method H  76

H 1

1 — 170-171 MH+ 504 r.t. 3.7′ Method A  77

H 1

1 — 179-180 MH+ 517 r.t. 5.8′ Method A  78

H 1

1 oxalate 100-101 MH+ 417 r.t. 3.4′ Method A  79

H 1

1 — 159-160 MH+ 490 r.t. 3.8′ Method A  80

H 1

1 — 160-161 MH+ 503 r.t. 8.5′ Method A  81

H 0

1 — 169-170 MH+ 473 r.t. 5.0′ Method A  82

H 0

1 — 172-173 MH+ 489 r.t. 5.17′ Method A  83

H 0

1 — 184-186 MH+ 471 r.t. 10.9′ Method A  84

H 0

1 — 188-189 MH+ 459 r.t. 4.81′ Method A  85

H 1

1 — 191-192 MH+ 489 r.t. 5.22′ Method A  86

H 0

1 — 189-190 MH+ 475 r.t. 4.97′ Method A  87

H 1

1 — 172-174 MH+ 505 r.t. 4.77′ Method A  88

H 1

1 HCl 275-278 MH+ 492 r.t. 4.65′ Method A  89

H 1

1 — 230-232 MH+ 513 r.t. 4.86′ Method A  90

H 1

1 — 215-217 MH+ 529 r.t. 5.07′ Method A  91

H 1

1 — 171-172 MH+ 484 r.t. 5.87′ Method A  92

H 1

1 — 130-131 MH+ 533 r.t. 5.75′ Method A  93

H 1

1 — 121-123 MH+ 429 r.t. 4.06′ Method A  94

H 1

1 — 184-185 MH+ 454 r.t. 5.35′ Method A  95

H 1

1 HCl — MH+ 483 r.t. 5.05′ Method A  96

H 1

1 — 153-154 MH+ 557 r.t. 6.5′ Method A  97

H 1

1 — 198-200 MH+ 498 r.t. 5.27′ Method  98

H 1

1 — 213-215 MH+ 452 r.t. 4.19′ Method I  99

H 1

1 oxalate  99-100 MH+ 487 r.t. 4.18′ Method I 100

H 1

1 — 235-237 MH+ 449 r.t. 4.6′ Method I 101

H 1

1 — 157-158 MH+ 481 r.t. 5.46′ Method I 102

H 1

1 — — MH+ 448 r.t. 4.78 Method I 103

H 1

1 — 112-113 MH+ 464 r.t. 5.17′ Method I 104

H 1

1 — 74-75 MH+ 487 r.t. 5.67′ Method I 105

H 1

1 — 177-178 MH+ 469 r.t. 4.8′ Method I 106

H 1

1 — 90-91 MH+ 503 r.t. 4.39′ Method I 107

H 1

1 — 92-93 MH+ 453 r.t. 5.26′ Method I 108

H 1

1 — 202-204 MH+ 436 r.t. 4.67′ Method I 109

H 1

1 — 220-222 MH+ 470 r.t. 4.93′ Method I 110

H 1

1 — 198-200 MH+ 480 r.t. 4.45′ Method I 111

H 1

1 — — MH+ 433 r.t. 3.62′ Method I 112

H 1

1 — 89-90 MH+ 487 r.t. 5.59′ Method I 113

H 1

1 — 80-81 MH+ 499 r.t. 5.3′ Method I 114

H 1

1 — 189-190 MH+ 483 r.t. 5.11′ Method I 115

H 1

1 — — MH+ 500 r.t. 4.83′ Method I 116

H 1

1 — 121-123 MH+ 501 r.t. 5.94′ Method I 117

H 1

1 — 90-93 MH+ 517 r.t. 4.86′ Method I 118

H 1

1 — 145-148 MH+ 502 r.t. 4.13′ Method I 119

H 1

1 oxalate 140-145 MH+ 514 r.t. 5.19′ Method I 120

H 1

1 oxalate 165-170 MH+ 513 r.t. 4.97′ Method I 121

H 1

1 — 94-95 MH+ 510 r.t. 4.95′ Method I 122

H 1

1 — 135-136 MH+ 496 r.t. 5.24′ Method I 123

H 1

1 — 101-102 MH+ 508 r.t. 5.1′ Method I 124

H 1

1 — 178-180 MH+ 511 r.t. 4.72′ Method I 125

H 1

1 — — MH+ 509 r.t. 4.71′ Method I

The compounds according to the invention underwent biochemical studies.

Cell Culture:

The SH-SY-5Y strain (human neuroblastoma) is conventionally cultured ina DMEM culture medium (Dulbecco's Modified Eagle's Medium) (Gibco BRL,France) containing FCS (5%) (fetal calf serum) (Boehringer Mannheim,Germany), sodium pyruvate (1 mM) and glutamine (4 mM) incollagen-covered culture flasks (Becton Dickinson, France).

The SK-N-BE parent strain (human neuroblastoma) and the clone Bep 75,stably expressing the complete form of the human p75^(NTR) receptor(SK-N-BE Bep 75) are conventionally cultured in an RPMI culture mediumcontaining FCS (5%), sodium pyruvate (1 mM) and glutamine (4 mM). Forthe SK-N-BE Bep 75 cells, hygromycin (200 μl/20 ml of medium) is addedas selection agent.

Study of the Dimerization of the p75^(NTR) Receptor Independently of itsLigand

The study of the dimerization of the p75^(NTR) receptor is performed ona cell suspension of the strain SK-N-BE Bep 75. The cells (2.5×10⁴cells/well) are placed in wells (96-well plate) for 24 hours, and thenpreincubated for 1 hour at 37° C. in the presence or absence of thecompounds according to the invention. Supernatent, obtained from aculture of human cells of HEK293 renal origin expressing, after 48 hoursof transfection, and secreting a soluble form of the p75^(NTR) receptor(extracellular part of the receptor) coupled to an alkaline phosphatase,the latter at a final concentration of 10 nM, is then added. Thequantification of the specific binding of the soluble receptor to thereceptor present on SK-N-BE Bep 75 cells is determined by measuring theenzyme activity of the alkaline phosphatase after incubation of thecells for 1 hour at 37° C. in the presence of the supernatant. Afterfiltering and transferring the filters into 24-well plates, the alkalinephosphatase activity is determined by adding CDP-Star chemoluminescentsubstrate (ready-to-use, Roche). The concentrations of the compoundsaccording to the invention that inhibit 50% (IC₅₀) of the dimerizationof the p75^(NTR) receptor are low, and range from 10⁻⁶ to 10⁻¹¹ M.

The compounds of formula (I) show activity in this test with IC₅₀ valuesranging from 10⁻⁶ to 10⁻¹¹ M.

For example, compounds 1, 14, 34 and 36 showed, respectively, an IC₅₀value of 0.08 nM, 1.09 nM, 0.94 nM and 20 nM.

Measurement of the Apoptosis

The cells (strains of human neuroblastomas SH-SY-5Y and SK-N-BE Bep 75)are placed in Petri dishes 35 mm in diameter (Biocoat collagenl, (10⁵cells/well)) in a suitable culture medium containing 5% FCS, for 24hours. The culture medium is then removed, the cells are rinsed with PBS(Dulbecco's Phosphate-buffered saline), and then either fresh mediumcontaining 5% FCS, or medium containing NGF (at a concentration of 10ng/ml), or beta-amyloid peptide (Aβ1-40) (at a concentration of 10 μM)is then added, in the presence or absence of the compounds according tothe invention. The apoptosis levels are measured 48 hours after thetreatments in the case of the strain SH-SY-5Y, and 24 hours later in thecase of the strain SK-N-BE Bep 75, by quantifying the cytoplasmichistones associated with the DNA fragments (cell death detection ELISA,Boehringer Mannheim, Germany). The apoptosis levels are expressed as theamount of oligonucleosomes/10⁵ cells. Each value corresponds to theaverage of 9 experimental points distributed over 3 independentexperiments.

The compounds of formula (I) show activity in this test, with IC₅₀values ranging from 10⁻⁶ to 10⁻¹¹M.

For example, compounds 19, 14 and 34 showed, respectively, an IC₅₀ valueof 1.07 nM, 1.33 nM and 3.39 nM.

Thus, the binding of the compounds according to the invention top75^(NTR) receptor is reflected, firstly, at the biochemical level byinhibition of dimerization of the receptor induced by the neurotrophins,or independently of the ligand, and, secondly, at the cellular level, byinhibition of the proapoptotic effect mediated by the p75^(NTR)receptor.

Thus, according to one of the subjects of the present invention, thecompounds of formula (I) show very advantageous inhibitory activity onthe dimerization of the p75^(NTR) receptor independently of its ligand.

The compounds according to the invention may thus be used for thepreparation of medicaments, in particular medicaments intended forpreventing or treating any pathology in which the p75^(NTR) receptor isinvolved, more particularly those indicated hereinbelow.

The compounds according to the invention may also be used for preventingor treating any pathology in which the p75^(NTR) receptor is involved,more particularly those indicated hereinbelow.

Thus, according to another of its aspects, a subject of the invention ismedicaments comprising a compound of formula (I), or an addition saltthereof with a pharmaceutically acceptable acid.

Thus, the compounds according to the invention may be used, in man oranimals, in the treatment or prevention of various p75^(NTR)-dependentcomplaints such as central and peripheral neurodegenerative diseases,for instance senile dementia, epilepsy, Alzheimer's disease, Parkinson'sdisease, Huntington's chorea, Down's syndrome, prion diseases, amnesia,schizophrenia, depression, bipolar disorder; amyotrophic lateralsclerosis, multiple sclerosis; cardiovascular complaints, for instancepost-ischemic heart damage, cardiomyopathies, myocardial infarction,cardiac insufficiency, cardiac ischemia, cerebral infarction; peripheralneuropathies (of diabetic, traumatic or iatrogenic origin); optic nerveand retinal damage (retinal pigment degeneration, glaucoma); retinalischemia; macular degeneration, spinal cord trauma and cranial trauma;atherosclerosis; stenoses, wound healing disorders; alopecia.

The compounds according to the invention may also be used in thetreatment of pancreatitis and hepatic fibrosis.

The compounds according to the invention may also be used in thetreatment of cancers, for instance lung cancer, thyroid cancer,pancreatic cancer, prostate cancer, small intestine cancer, colorectalcancer and breast cancer, and in the treatment of tumors, metastases andleukemias.

The compounds according to the invention may also be used in thetreatment of respiratory disorders, for instance pulmonary inflammation,allergy and asthma, and chronic obstructive pulmonary disease.

The compounds according to the invention may also be used in thetreatment of cutaneous pain (of the skin, of the subcutaneous tissuesand associated organs), somatic pain, visceral pain (of the circulatory,respiratory, gastrointestinal or urogenital system) and neurologicalpain.

The compounds according to the invention may be used in the treatment ofchronic neuropathic and inflammatory pain and in the treatment ofautoimmune diseases, such as rheumatoid arthritis.

The compounds according to the invention may also be used in thetreatment of diseases such as ankylosing spondylitis, psoriaticarthritis and plaque psoriasis.

The compounds according to the invention may also be used in thetreatment of bone fractures, and in the treatment or prevention of bonediseases such as osteoporosis.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active principle, a compoundaccording to the invention. These pharmaceutical compositions contain aneffective dose of at least one compound according to the invention, or apharmaceutically acceptable salt of said compound, and also at least onepharmaceutically acceptable excipient.

Said excipients are chosen, according to the pharmaceutical form and thedesired mode of administration, from the usual excipients known to thoseskilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or the salt thereof, may beadministered in a unit administration form, as a mixture with standardpharmaceutical excipients, to man and animals for the treatment orprevention of the above disorders or diseases.

The appropriate unit forms of administration include oral forms such astablets, soft or hard gel capsules, powders, granules and oral solutionsor suspensions, sublingual, buccal, intratracheal, intraocular,intranasal and inhalation administration forms, topical administrationforms, parenteral administration forms such as transdermal,subcutaneous, intramuscular or intravenous administration forms, rectaladministration forms and implants. For topical application, thecompounds according to the invention may be used in creams, gels,ointments or lotions.

By way of example, a unit form of administration of a compound accordingto the invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mgCroscaramellose sodium 6.0 mg Corn starch 15.0 mgHydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg

The dose of active principle administered per day may range from 0.01 to100 mg/kg, in one or more dosage intakes, and preferentially 0.02 to 50mg/kg. In general, the daily dose of the compound of the invention willbe the lowest effective dose of the compound that is capable ofproducing a therapeutic effect.

There may be particular cases in which higher or lower dosages areappropriate; such dosages do not depart from the scope of the invention.According to the usual practice, the dosage that is appropriate to eachpatient is determined by the doctor according to the mode ofadministration and the weight and response of said patient.

According to another of its aspects, the present invention also relatesto a method for treating the pathologies indicated above, whichcomprises the administration, to a patient, of an effective dose of acompound according to the invention, or a pharmaceutically acceptablesalt thereof.

What is claimed is:
 1. A method for preventing or treating a pathologyselected from the group consisting of central and peripheralneurodegenerative diseases, senile dementia, epilepsy, Alzheimer'sdisease, Parkinson's disease, Huntington's chorea, Down's syndrome,prion diseases, amnesia, schizophrenia, depression, bipolar disorder,amyotrophic lateral sclerosis, multiple sclerosis, cardiovasculardisorders, post-ischemic heart damage, cardiomyopathies, myocardialinfarction, cardiac insufficiency, cardiac ischemia, cerebralinfarction, peripheral neuropathies, optic nerve and retinal damage,retinal pigment degeneration, glaucoma, retinal ischemia, maculardegeneration, spinal cord trauma, cranial trauma, atherosclerosis,stenosis, wound healing disorders, alopecia, pancreatitis, hepaticfibrosis, cancers, tumors, metastases, leukemias, respiratory disorders,pulmonary inflammation, allergy, asthma, chronic obstructive pulmonarydisease, cutaneous, somatic, visceral and neurological pain, chronicneuropathic and inflammatory pain, autoimmune diseases, rheumatoidarthritis, ankylosing spondylitis, psoriatic arthritis, plaquepsoriasis, bone fractures, bone diseases and osteoporosis; said methodcomprising administering to a patient in need thereof an effective doseof a compound of formula (I):

wherein: n represents 1 or 2; m represents 0 or 1; A represents a fusedheterocyclic group of formula (Y):

and B represents a hydrogen atom; or A represents a hydrogen atom; and Brepresents a fused heterocyclic group of formula (Y):

wherein the fused heterocycle of formula Y is attached to the rest ofthe molecule via any of the available carbon atoms, and wherein Ucompletes: either an aromatic or saturated 6-atom nucleus, containingone or two nitrogen atoms, the nucleus possibly being substituted withone or two halogen atoms, one or two (C1-C4)alkyl or (C1-C4)alkoxygroups, or one or two perfluoroalkyl radicals; or an aromatic orsaturated 5-atom nucleus, containing a nitrogen, oxygen or sulfur atom,the nucleus optionally being substituted with one or two (C1-C4)alkylgroups; X and X1 represent CH or N; R and R1 are located on any of theavailable positions, and independently represent a hydrogen atom, ahalogen atom, a group (C1-C4)alkyl, (C1-C4)alkoxy, a perfluoroalkyl ortrifluoromethoxy radical, a cyano or a group COOH, COOalkyl, CONR3R4 orNHCOR3; —W— is a nitrogenous heterocycle chosen from:

1-2 represents 1 or 2; 1-3 represents 1, 2 or 3; R2 represents a groupof formula:

wherein R5 and R6, located on any of the available positions,independently represent a hydrogen atom, a halogen atom, a group(C1-C4)alkyl or (C1-C4)alkoxy, a trifluoromethyl or trifluoromethoxyradical, a cyano or a group COOH, COOalkyl, COOcycloalkyl, SOalkyl,SO₂alkyl, CONR3R4, NR3R4 or NHCOR3; or one of R5 and R6 represents aheterocycle chosen from:

Z represents an oxygen or sulfur atom; and R3 and R4 represent ahydrogen or a group C1-C6 alkyl; or a pharmaceutically acceptable saltthereof.
 2. The method according to claim 1, wherein for the compound offormula (I): A represents a fused heterocyclic group of formula (Y)

and B represents a hydrogen atom; or A represents a hydrogen atom; and Brepresents a fused heterocyclic group of formula (Y)

wherein the fused heterocycle of formula Y is attached to the rest ofthe molecule via any of the available carbon atoms of the benzenenucleus; a pharmaceutically acceptable salt thereof.
 3. The methodaccording to claim 1, wherein for the compound of formula (I): R and R1,located on any of the available positions, independently represent ahydrogen atom, a halogen atom or a group (C₁-C₄)alkyl or COOalkyl; or apharmaceutically acceptable salt thereof.
 4. The method according toclaim 1, wherein for the compound of formula (I): —W— is a nitrogenousheterocycle chosen from:

and R3 and R4 represent a hydrogen atom or a methyl group; or apharmaceutically acceptable salt thereof.
 5. The method according toclaim 1, wherein for the compound of formula (I): R2 represents a groupof formula:

R5 and R6, located on any of the available positions, independentlyrepresent a hydrogen atom, a trifluoromethyl radical or a group COOH,COOalkyl or COOcycloalkyl; or one of the groups R5 and R6 represents aheterocycle chosen from:

Z represents an oxygen or sulfur atom; and R3 and R4 represent ahydrogen or a methyl group; or a pharmaceutically acceptable saltthereof.
 6. The method according to claim 1, wherein the compound offormula (I) is selected from the group consisting of:1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(3,5-dimethyl-2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-yl)ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(8-pyrimidin-2-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(8-pyrimidin-2-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,5R)-2,5-dimethyl-2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-yl)ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,5R)-2,5-dimethyl-2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-yl)ethanone;1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-7-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-[4-(2-propylbenzo[b]thiophen-7-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[5-(5-trifluoromethylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone;1-(4-benzo[b]thiophen-6-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-(8-pyrimidin-2-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;4-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,6R)-2,6-dimethyl-4-quinolin-2-ylpiperazin-1-yl)ethanone;1-(4-quinolin-8-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone;1-(4-benzofuran-3-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;1-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;1-(4-benzo[b]thiophen-3-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;4-{2-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)ethanone;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;2-((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)ethanone;1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)ethanone;4-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;5-{(3S,5R)-4-[2-(4-benzo[b]thiophen-4-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}pyridine-2-carboxylicacid;4-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(6-trifluoromethylpyridin-3-yl)piperazin-2-one;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;Methyl5-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}pyridine-2-carboxylate;Methyl6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinate;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)ethanone;6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinicacid;6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinicacid; Methyl6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinate;6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinicacid;4-[2-(4-benzofuran-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;Methyl6-((3S,5R)-3,5-dimethyl-4-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-1-yl)nicotinate;6-((3S,5R)-3,5-dimethyl-4-{2-[4-(2-methylbenzo[b]thiophen-5-yl-)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-1-yl)nicotinicacid;1-(5-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;Ethyl6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinate;Methyl6-{3-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;Methyl7-(1-{2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]acetyl}-1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene-2-carboxylate;Methyl5-(1-{2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]acetyl}-1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene-2-carboxylate;2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-[4-(2-propylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;Methyl6-{3-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;Methyl6-{3-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;6-{3-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinicacid;2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-[4-(7-fluorobenzofuran-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;1-[4-(2,3-dimethylbenzofuran-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-(4-quinolein-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone;1-(4-benzofuran-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-yl)ethanone;Methyl6-{3-[2-oxo-2-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-pyridin-1-yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;Methyl6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinate;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(4-pyridin-3-yl-[1,4]diazepan-1-yl)ethanone;6-{3-[2-oxo-2-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-pyridin-1-yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinicacid;6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinicacid; Methyl6-{3-[2-(3-benzofuran-7-yl-2,5-dihydropyrrol-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;Methyl6-{3-[2-(3-benzo[b]thiophen-7-yl-2,5-dihydropyrrol-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;4-[2-(3-benzofuran-7-yl-2,5-dihydropyrrol-1-yl)-2-oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;6-{3-[2-(4-benzofuran-7-yl-2,3-dihydropyrrol-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinicacid;6-{3-[2-(5-benzo[b]thiophen-7-yl-3,4-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinicacid;6-{3-[2-(4-benzo[b]thiophen-7-yl-2,3-dihydropyrrol-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinicacid; Methyl6-(3-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinate;2-{(3S,5R)-4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}pyrimidine-5-carboxylicacid;3-(6-{3-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl)}pyridin-3-yl)-4H-[1,2,4]oxadiazol-5-one;3-(6-{3-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}pyridin-3-yl)-4H-[1,2,4]oxadiazol-5-one;6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinonitrile;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-(3-chloro-5-trifluoromethylpyridin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(8-pyridin-3-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;6-{3-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinonitrile;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[5-(5-trifluoromethylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone;cyclobutyl6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinate;2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-(4-quinolin-2-ylpiperazin-1-yl)ethanone;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]ethanone;2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-(5-chloropyridin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2R,5S)-2,5-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(6-trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(4-quinolin-2-ylpiperazin-1-yl)ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(7-chloro-quinolin-4-yl)piperazin-1-yl]ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-chloro-pyridin-2-yl)piperazin-1-yl]ethanone;2-[4-(6-chloropyridin-2-yl)piperazin-1-yl]-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;2-((2S,6R)-2,6-dimethyl-4-quinolin-2-yl-piperazin-1-yl)-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(4-pyridin-3-yl[1,4]diazepan-1-yl)ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5,6-dichloropyridin-2-yl)piperazin-1-yl]ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(6-bromopyridin-2-yl)piperazin-1-yl]ethanone;1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-(4-quinolin-2-ylpiperazin-1-yl)ethanone;1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[5-(6-trifluoromethylpyridazin-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone;1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;2-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;4-[2-oxo-2-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-pyridin-1-yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-dimethyl-4-(5-thiazol-2-ylpyridin-2-yl)piperazin-1-yl]ethanone;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-{(2S,6R)-2,6-dimethyl-4-[5-(2-methyl-2H-tetrazol-5-yl)pyridin-2-yl]piperazin-1-yl}ethanone;2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone;4-[2-oxo-2-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;1-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-{8-[5-(1-methyl-1H-tetrazol-5-yl)pyridin-2-yl]-3,8-diazabicyclo[3.2.1]oct-3-yl}ethanone;and1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-(5-methanesulfonyl-pyridin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;or a pharmaceutically acceptable salt thereof.
 7. The method accordingto claim 1, wherein the pathology is selected from the group consistingof senile dementia, epilepsy, Alzheimer's disease, Parkinson's disease,Huntington's chorea, Down's syndrome, prion diseases, amnesia,schizophrenia, depression, bipolar disorder, amyotrophic lateralsclerosis, multiple sclerosis, post-ischemic heart damage,cardiomyopathies, myocardial infarction, cardiac insufficiency, cardiacischemia, cerebral infarction, peripheral neuropathies, optic nerve andretinal damage, retinal pigment degeneration, glaucoma, retinalischemia, macular degeneration, spinal cord trauma, cranial trauma,atherosclerosis, stenosis, wound healing disorders, and alopecia.
 8. Themethod according to claim 1, wherein the pathology is selected from thegroup consisting of pancreatitis and hepatic fibrosis.
 9. The methodaccording to claim 1, wherein the pathology is cancer wherein the canceris selected from the group consisting of lung cancer, thyroid cancer,pancreatic cancer, prostate cancer, small intestine cancer, colorectalcancer and breast cancer.
 10. The method according to claim 1, whereinthe pathology is selected from the group consisting of pulmonaryinflammation, allergy, asthma, and chronic obstructive pulmonarydisease.
 11. The method according to claim 1, wherein the pathology isselected from the group consisting of cutaneous, somatic, visceral andneurological pain.
 12. The method according to claim 1, wherein thepathology is selected from the group consisting of chronic neuropathicand inflammatory pain, and rheumatoid arthritis.
 13. The methodaccording to claim 1, wherein the pathology is selected from the groupconsisting of ankylosing spondylitis, psoriatic arthritis, and plaquepsoriasis.
 14. The method according to claim 1, wherein the pathology isselected from bone fractures, bone diseases and osteoporosis;